Fatal polysubstance intoxications involving inhalation of nitazene analogues: identification of fluetonitazepyne and 5-methyl etodesnitazene

The illicit opioid market has undergone notable diversification, with 2-benzylbenzimidazoles (nitazenes) representing an increasingly prevalent class of non-fentanyl synthetic opioids. These compounds challenge forensic toxicology through marked µ-opioid receptor potency and rapid structural evolution, often undetected by routine immunoassay screening. We report two fatal polysubstance intoxications involving inhalation of nitazene analogues via vaping devices, identified in biological matrices. GC-MS-based identification was corroborated by untargeted LC-HRMS screening with in silico data mining and confirmed against certified reference standards. Case 1 involved a 40-year-old male found deceased after an estimated 2–3 days without contact. Fluetonitazepyne was quantified at 0.58 ng/mL in peripheral blood alongside ethanol (0.55 g/kg), supra-therapeutic citalopram (340 ng/mL), sub-therapeutic lithium, and cannabinoid metabolites, concordant with a recovered vaping vial containing the same nitazene. Death could not be established with certainty; based on toxicological findings, it was most likely acute fluetonitazepyne intoxication in the presence of central nervous system (CNS) depressants. Case 2 concerned a 22-year-old male with a witnessed cardiorespiratory arrest following inhalation from a vaping device confirmed to contain 5-methyl etodesnitazene. Despite bystander cardiopulmonary resuscitation (CPR), naloxone administration (1.6 mg), and intensive care, he died from acute anoxic encephalopathy approximately 24 h later. Ante mortem peripheral blood confirmed 5-methyl etodesnitazene at 3.3 ng/mL alongside barbital at toxic concentrations (39 mg/L). Concurrent CNS depressant exposure potentiated fatal respiratory depression, more clearly established in Case 2. These cases document the lethal potential of emerging nitazene analogues and the value of untargeted HRMS-based screening in the absence of certified reference standards.